Celiac disease (CD) is a major public health problem affecting up to 1% of the general population and leading to significant morbidity and mortality. In the U.S., CD is still under-diagnosed due to low awareness and lack of a comprehensive screening program in high-risk groups. Our unique large prospective study of children at high-risk of CD (R01 DK50979, 9/1995-11/2006, M. Rewers, P.I.) has responded to many of the research priorities identified by the 2004 NIH Consensus Development Conference on Celiac Disease (1). This competing renewal application proposes to take to a new level characterization of genetic determinants of variable CD phenotypes to develop optimal approaches to screening, follow-up and prevention of CD. The proposed study aims to: SPECIFIC AIMS: 1. Determine the incidence and the natural history of celiac disease in children aged 10-15, by prospective annual testing for TG IgA autoantibodies and follow-up intestinal biopsy in positive subjects identified in already established cohorts: 1.1. General population children with high risk HLA-DR,DQ genotypes (n=1,346) 1.2. Type 1 diabetic (T1D) children (n=2,800) 1.3. Non-diabetic first degree relatives of T1D patients (n=1,065) 2. Answer a fundamental question whether there are genetic polymorphisms other than the HLA-DQ alleles,within or outside the MHC region that confer major risk for CD, in 2.1. Nested case-control association studies of candidate genetic markers. 2.2. Family-based multi-SNP analyses of MHC haplotypes associated with celiac disease and T1D. 3. In a nested case-control study using novel markers, e.g., zonulin, Glb1 autoantibodies, characterize determinants of apparent window of susceptibility to dietary gluten. 4. Assess the impact of seropositivity for TG IgA on intestinal mucosa morphology, intestinal permeability,growth and development, bone mineralization and micronutrient deficiencies in screening detected children with and without T1D.